Caffeine seems to be good for preterm infants. We know that it reduces the frequency of apnea in the this population and moreover facilitates weaning off the ventilator in a shorter time frame than if one never received it at all. The earlier you give it also seems to make a difference as shown in the Cochrane review on prophylactic caffeine. When given in such a fashion the chances of successful extubation increase. Less time on the ventilator not surprisingly leads to less chronic lung disease which is also a good thing.
I have written about caffeine more than once though so why is this post different? The question now seems to be how much caffeine is enough to get the best outcomes for our infants. Last month I wrote about the fact that as the half life of caffeine in the growing preterm infant shortens, our strategy in the NICU might be to change the dosing of caffeine as the patient ages. Some time ago though I wrote about the use of higher doses of caffeine and in the study analyzed warned that there had been a finding of increased cerebellar hemorrhage in the group randomized to receive the higher dosing. I don’t know about where you work but we are starting to see a trend towards using higher caffeine base dosing above 5 mg/kg/d. Essentially, we are at times “titrating to effect” with dosing being as high as 8-10 mg/kg/d of caffeine base.
Does it work to improve meaningful outcomes?
This month Vliegenthart R et al published a systematic review of all RCTs that compared a high vs low dosing strategy for caffeine in infants under 32 weeks at birth; High versus standard dose caffeine for apnoea: a systematic review. All told there were 6 studies that met the criteria for inclusion. Low dosing (all in caffeine base) was considered to be 5- 15 mg/kg with a maintenance dose of 2.5 mg/kg to 5 mg/kg. High dosing was a load of 5 mg/kg to 40 mg/kg with a maintenance of 2.5 mg/kg to 15 mg/kg. The variability in the dosing (some of which I would not consider high at all) makes the quality of the included studies questionable so a word of warning that the results may not truly be “high” vs “low” but rather “inconsistently high” vs. “inconsistently low”.
The results though may show some interesting findings that I think provide some reassurance that higher dosing can allow us to sleep at night.
On the positive front, while there was no benefit to BPD and mortality at 36 weeks PMA they did find if they looked only at those babies who were treated with caffeine greater than 14 days there was a statistically significant difference in both reduction of BPD and decreased risk of BPD and mortality. This makes quite a bit of sense if you think about it for a moment. If we know that caffeine improves the chances of successful extubation and we also know it reduces apnea, then who might be on caffeine for less than 2 weeks? The most stable of babies I would expect! These babies were all < 32 weeks at birth. What the review suggests is that those babies who needed caffeine for longer durations benefit the most from the higher dose. I think I can buy that.
On the adverse event side, I suppose it shouldn’t surprise many that the risk of tachycardia was statistically increased with an RR of 3.4. Anyone who has explored higher dosing would certainly buy that as a side effect that we probably didn’t need an RCT to prove to us. Never mind that, have you ever taken your own pulse after a couple strong coffees in the morning?
What did it not show?
It’s what the study didn’t show that is almost equally interesting. The cerebellar hemorrhages seen in the study I previously wrote about were not seen at all in the other studies. There could be a lesson in there about taking too much stock in secondary outcomes in small studies…
Also of note, looking at longer term outcome measures there appears to be no evidence of harm when the patients are all pooled together. The total number of patients in all of these studies was 620 which for a neonatal systematic review is not bad. A larger RCT may be needed to conclusively tell us what to do with a high and low dosing strategy that we can all agree on. What do we do though in the here and now? More specifically, if you are on call tomorrow and a baby is on 5 mg/kg/d of caffeine already, will you intubate them if they are having copious apneic events or give them a higher dose of caffeine when CPAP or NIPPV that they are already on isn’t cutting it? That is where the truth about how you feel about the evidence really comes out. These decisions are never easy but unfortunately you sometimes have to make a decision and the perfect study hasn’t been done yet. I am not sure where you sit on this but I think this study while certainly flawed gives me some comfort that nothing is truly standing out especially given the fact that some of the “high dose” studies were truly high. Will see what happens with my next patient!

Dear Colleagues,
We are organizing the next annual neonatal simulation conference in September on the 26th and 27th of September 2017 at the Grand Harbour Hotel Southampton in the summer. The conference has a multidisciplinary theme of ‘Simulating Together to Improve Neonatal Outcomes’. We are looking to showcase work done by you in the field of neonatal simulation and technology enhanced learning. There are 8 workshops, 16 plenary sessions and we will be accepting podium presentations and posters as well. There will be dedicated sessions covering simulation technology, debriefing, new mannikins, moulage, manikin modification and barriers to the uptake of simulation. This conference is about your work, let us learn from you. Amongst the awards to be won are ‘Young Investigator of the Year’, ‘Multidisciplinary Simulation Team of the Year’, ‘Application of Technology Enhanced Learning in Neonatal Care’ and ‘NEOSIMTEL CHAMPIONS’.
For further information, speakers, and an abstract form or brochure please visit http://www.mproveonline.com/conference
We are currently inviting abstracts for all the above including workshops. If you have a neonatal simulation programme and would like to present your work, or are a multiprofessional neonatal team looking to highlight technology enhanced learning in neonatal education please apply through the abstract form.
Best Wishes
Dr Alok Sharma (aloksharma@nhs.net) & Dr Ranjit Gunda (drgunda@gmail.com)

I have often said that if this came to pass as a mandatory requirement that I would make an announcement shortly thereafter that I was moving on to another career. I think people thought I was kidding but I can put in writing for all to see that I am serious! The subject has been discussed for some time as I can recall such talks with colleagues both in my current position and in other centres. The gist of the argument for staying in-house is that continuity is improved over that period and efficiency gained by avoiding handovers twice a day . How many times have you heard at signover that extubation will be considered for the following morning or to keep the status quo for another issue such as feeding until the next day. No doubt this is influenced by a new set of eyes being in the unit and a change in approach to being one of “putting out fires” overnight. The question then is whether having one Neonatologist there for 24 hours leads to better consistency and with it better outcomes. With respect to PICUs the AAP has previously recommended that 24 hour in-house coverage by an intensivist be the standard so should Neonatology follow suit?
A Tale of Two Periods
My friends in Calgary, Alberta underwent a change in practice in 2001 in which they transitioned from having an in-house model of Neonatologist coverage for 24 hours a day to one similar to our own centres where the Neonatologist after handover late afternoon could take call from home. An article hot off the presses entitled Twenty-Four hour in-house neonatologist coverage and long-term neurodevelopmental outcomes of preterm infants seeks to help answer this question. The team undertook a retrospective analysis of 387 infants born at < 28 weeks gestational age during the periods of 1998-2000 (24 hour period, N=179 infants) vs 2002 – 2004 (day coverage, N= 208 infants) with the goal of looking at the big picture being follow-up for developmental outcome at 3 years. This is an important outcome as one can look at lots of short term outcomes (which they also did) but in the end what matters most is whether the infants survive and if they do are they any different in the long term.
As with any such study it is important to look at whether the infants in the two periods are comparable in terms of risk factors for adverse outcome. Some differences do exist that are worth noting.
Increased risk factors in the 24 hour group
Chorioamnionitis
Maternal smoking
Smaller birthweight (875 vs 922 g)
Confirmed sepsis (23% vs 14%)
Postnatal steroids (45% vs 8%) – but duration of ventilation longer in the day coverage group likely due to less postnatal steroids ( 31 vs 21 days)
All of these factors would predict a worse outcome for these infants but in the end for the primary outcome of neurodevelopmental impairment there was no difference. Even after controlling for postnatal steroids, birth weight, sex and 5 minute apgar score there was still no difference.
What might this mean?
Looking at this with a glass is half full view one might say that with all of the factors above predicting worse outcome for infants, the fact that the groups are not different in outcome may mean that the 24 hour model does indeed confer a benefit. Maybe having a Neonatologist around the clock means that care is made that much better to offset the effect of these other risk factors? On the other hand another explanation could also be that the reason there is no difference is that the sample just isn’t big enough to show a difference. In other words the size of the study might be underpowered to find a difference in developmental outcome.
One of the conclusions in this study is that the presence of a Neonatologist around the clock may have led to earlier extubation and account for the nearly 10 day difference in duration of ventilation. While I would love to believe that for personal reasons I don’t think we can ignore the fact that in the earlier epoch almost 50% of the babies received postnatal steroids compared to 8% in the later period. Postnatal steroids work and they do so by helping us get babies off ventilators. It is hard to ignore that point although I woudl like to take credit for such an achievement.
For now it would appear that I don’t feel compelled to stay overnight in the hospital unless it is necessary due to patient condition necessitating me having my eye on the patient. I am not sure where our field will go in the future but for now I don’t see the evidence being there for a change in practice. With that I will retire to my bedroom while I am on call and get some rest (I hope).

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CALL FOR SUBMISSIONS!
If any neonatologists have a manuscript that has been collecting dust that you believe in but have had difficulty getting published, let us know. We are starting up a new electronic journal in the field of neonatology that will be completely on-line, open-source, and free of charge.
Getting papers published is getting harder and harder these days, even those papers that are well-designed but may lack a few things or don't show any statistical significance (i.e. negative studies). We hope to launch the journal in time for PAS/SPR in May. Feel free to email me at eNeoResearch@gmail.com if you have any questions or want to know more about this new Neonatology journal

Our first conference is to be held in Portsaid Egypt, at the 21 st - 23 rd of October 2010, it's a conjoint effort from Portsaid NICU workers to help raise the quality of life for our neonates. The title will be Perinatal medicine, so obstetricians will participate also in this conference in our charming city of Portsaid on Suez Canal, hope you share this acitivity with us
M Osama Hussein
El Nasr NICU Portsaid